TY - JOUR
T1 - A Phase Ib Study of the VEGF Receptor Tyrosine Kinase Inhibitor Tivozanib and Modified FOLFOX-6 in Patients With Advanced Gastrointestinal Malignancies
AU - Oldenhuis, Corina N.
AU - Loos, Walter J.
AU - Esteves, Brooke
AU - van Doorn, Leni
AU - Cotreau, Monette M.
AU - Strahs, Andrew L.
AU - den Hollander, Martha W.
AU - Gietema, Jourik A.
AU - de Vries, Elisabeth G. E.
AU - Eskens, Ferry A. L. M.
PY - 2015/3
Y1 - 2015/3
N2 - Combining a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen with antiangiogenic therapy is a standard treatment option in advanced colorectal cancer. In this phase Ib study, safety, pharmacokinetics, and antitumor activity of tivozanib with mFOLFOX-6 were assessed. Tivozanib could be combined at its recommended dose Of 1.5 mg with mFOLFOX-6, demonstrating antitumor activity, A randomized study in advanced colorectal Cancer comparing bevacizumab and tivozanib with mFOLFOX-6 has been performed.Background: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. Patients and Methods: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. Results: Thirty patients were assigned to tivozanib 0.5 mg (n = 9); 1.0 mg (n = 3); or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8); fatigue (n = 8), and neutropenia (n = 6): MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. Conclusion: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.
AB - Combining a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen with antiangiogenic therapy is a standard treatment option in advanced colorectal cancer. In this phase Ib study, safety, pharmacokinetics, and antitumor activity of tivozanib with mFOLFOX-6 were assessed. Tivozanib could be combined at its recommended dose Of 1.5 mg with mFOLFOX-6, demonstrating antitumor activity, A randomized study in advanced colorectal Cancer comparing bevacizumab and tivozanib with mFOLFOX-6 has been performed.Background: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. Patients and Methods: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. Results: Thirty patients were assigned to tivozanib 0.5 mg (n = 9); 1.0 mg (n = 3); or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8); fatigue (n = 8), and neutropenia (n = 6): MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. Conclusion: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.
KW - Angiogenesis
KW - Clinical study
KW - mFOLFOX-6
KW - Pharmacokinetics
KW - Safety
KW - ENDOTHELIAL GROWTH-FACTOR
KW - METASTATIC COLORECTAL-CANCER
KW - RENAL-CELL CARCINOMA
KW - SOLID TUMORS
KW - CHEMOTHERAPY
KW - COMBINATION
KW - 5-FLUOROURACIL
KW - OXALIPLATIN
KW - CEDIRANIB
KW - EFFICACY
U2 - 10.1016/j.clcc.2014.12.001
DO - 10.1016/j.clcc.2014.12.001
M3 - Article
SN - 1533-0028
VL - 14
SP - 18
EP - 24
JO - Clinical Colorectal Cancer
JF - Clinical Colorectal Cancer
IS - 1
ER -